Non-steroidal anti-inflammatory drugs (NSAIDs) are a class of therapeutic agents that are widely used for their anti-inflammatory and anti-pyretic properties to treat human distress and disease. Exemplary NSAIDs include aspirin, ibuprofen, acetaminophen, indomethacin, naproxen, and others.
The anti-inflammatory and anti-pyretic activities of NSAIDs derive from the ability of these compounds to bind to and inhibit the actions of the cyclooxygenase (COX) enzymes. COX activity originates from two distinct and independently regulated enzymes, termed cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2; see Dewitt & Smith, 1988; Yokoyama & Tanabe, 1989; Hla & Neilson, 1992). COX-1 is a constitutive isoform and is mainly responsible for the synthesis of cytoprotective prostaglandin in the gastrointestinal (GI) tract and for the synthesis of thromboxane, which triggers aggregation of blood platelets (Allison et al., 1992). On the other hand, COX-2 is inducible and short-lived. Its expression is stimulated in response to endotoxins, cytokines, and mitogens (Kujubu et al., 1991; Lee et al., 1992; O'Sullivan et al., 1993). NSAIDs exhibit varying selectivity for COX-1 and COX-2 but, in general, most display inhibitory activity towards both enzymes (Meade et al., 1993).
Inflammation and inflammatory responses have been associated with various diseases and disorders. For example, the brains of subjects with Alzheimer's disease (AD) are characterized by the accumulation of amyloid plaques accompanied by cellular and molecular markers of inflammatory responses. AD is the most common cause of dementia in the elderly, resulting in enormous costs to individuals and to society, both in terms of medical care and non-economic losses. As the population ages, it is undeniable that AD and related neurological disorders will become an ever-increasing medical and societal burden. What is needed, then, are new and better therapeutics that can be used to prevent and treat age-related neurological disorders.
Interestingly, epidemiological studies have suggested that long-term treatment with NSAIDs might provide a protective effect against the development of AD. Initially, it was believed that the protective effect derived from the anti-inflammatory actions of NSAIDs, but this hypothesis has recently been questioned. Several recent reports suggest instead that the protective effects are independent of the ability of NSAIDs to inhibit cyclooxygenases. Thus, treatment with NSAIDs might be useful to decrease the incidence and/or the severity of AD and related disorders.
Long-term use of NSAIDs is not without risks, however. In particular, most NSAIDs, particularly those that are inhibitors of COX-1, are associated with significant GI toxicities. As such, the long-term use of these drugs must be approached with caution. This requires a careful balance between the use of NSAIDs for their potential benefits vis-à-vis neurological disorders and the GI toxicity associated with their use. A more favorable approach would be to find or create new derivatives of NSAIDs that retain their protective effects but do not cause debilitating and potentially fatal toxicities.
One potential approach would be to employ NSAIDs that are specific for COX-2. Several such NSAIDs have been produced, including celecoxib, valdecoxib (CELEBREX™ and BEXTRA™, respectively; Pfizer Inc., New York, N.Y., United States of America), rofecoxib, etoricoxib (VIOXX™ and ARCOXIA™, respectively; Merck and Co., Inc., Whitehouse Station, N.J., United States of America), and lumiracoxib (PREXIGE®; Novartis Pharmaceuticals Corporation, East Hanover, N.J., United States of America). Unfortunately, recent evidence indicates that these COX-2-specific inhibitors do not provide any protective effect against the development of AD. In both in vivo and in vitro assays, neither celecoxib nor rofecoxib appeared capable of inhibiting the production of the Aβ42 protein, the cleavage product of the amyloid precursor protein (APP) believed to be responsible for the formation of amyloid plaques. Accordingly, it appears that simply using COX-2-specific NSAIDs is unlikely to provide the protective effects currently seen with other non-specific NSAIDs.
Additional evidence seems to suggest that the protective effects afforded by certain NSAIDs, such as ibuprofen, sulindac sulfide, and indomethacin (all non-specific NSAIDs), might not be related to their COX-inhibition activities, and thus might be related to the abilities of these NSAIDs to interact with other polypeptides present in the central nervous system (CNS). Two such polypeptides are the class of peroxisome proliferators-activated receptors (PPARs) and γ-secretase. For example, PPARs, particularly PPARγ, have been implicated in mediating differentiation of adipocytes and regulating fat metabolism. Additionally, PPARγ has been associated with various pathological conditions related to atherosclerosis, inflammation, obesity, diabetes, cancer, the immune response, and ageing. See Kersten et al., 2000; Celi & Shuldiner, 2002. γ-secretase, on the other hand, appears to be the main enzyme responsible for the production of Aβ42 from APP, and thus has a critical role in the pathogenesis of AD.
What are needed, then, are new derivatives of NSAIDs that are less toxic than the parent NSAIDs, yet retain the abilities of the parents to modulate the activities of, for example, PPARs and/or γ-secretase. This and other needs are addressed by the compositions and methods of the presently disclosed subject matter.